Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

EDNRB : Waardenburg syndrome type 4A

HGNC:3180 | MONDO_0010192
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10 3 3.5 3.5
Issa S et al. 2017 May (PMID:28236341);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3
1.5
1.5
Issa S et al. 2017 May (PMID:28236341);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 0

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 5 0 5 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Limited
11/28/2018
EXPERT CURATION (DATE)
Limited
05/08/2018
EVIDENCE SUMMARY
The relationship between EDNRB and autosomal dominant Waardenburg syndrome was evaluated using the ClinGen Clinical Validity Framework as of 12/14/2017. Per criteria outlines by the ClinGen Lumping and Splitting Working Group, the relationship between EDNRB and autosomal recessive Waardenburg syndrome has been assessed separately. Variants in EDNRB were first reported in humans with this disease as early as 2009 (Tuysuz et al., PMID 19764031). At least 6 missense, nonsense and frameshift variants have been reported in humans (Issa et al. 2017, PMID 28236341). Variants in this gene segregate with disease in multiple family members, however phenotypes vary among family members. A mouse model from Matsushima et al. 2002 shows a heterozygous Ednrb variant mouse without Waardenburg phenotypes, and a mouse model by Ida-Eto et al. 2011 shows recovered hearing in a heterozygous Ednrb variant mouse (PMIDs 11773966, 21715336). In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Hearing Loss Working Group on 5/8/2018.